Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors

The tumor pyruvate kinase M2 (PKM2) is involved in the glycolytic pathway of lung cancer and targeting this kinase has been observed to radiosensitize non-small cell lung cancer (NSCLC).An integration of in silico virtual screening and in vitro kinase assay was described to discover novel PKM2 inhibitors from a candidate library containing >400,000 commercially available compounds.The method is a stepwise screening scheme that first used empirical strategies to fast exclude those undruggable compounds in the library and then employed molecular docking and molecular dynamics (MD)-based rescoring to identify few potential hits. Subsequently, the computational findings were substantiated using a standard kinase assay protocol.Four compounds, i.e. nalidixic acid, indoprofen, hematoxylin and polydatin, were identified to inhibit PKM2 kinase at micromolar level, with IC50 values of 53, 21, 340 and 128 .M, respectively.Structural analysis revealed that hydrogen bonds, salt bridges, π-π stacking and hydrophobic forces co-confer high stability and strong specificity to PKM2-inhibitor binding.